The long noncoding RNA linc-NeD125 controls the expression of medulloblastoma driver genes by microRNA sponge activity
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Pietro Laneve1, Agnese Po2, Annarita Favia3, Ivano Legnini4, Vincenzo Alfano1,2, Jessica Rea4, Valerio Di Carlo4,11, Valeria Bevilacqua4,12, Evelina Miele1,13, Angela Mastronuzzi5, Andrea Carai6, Franco Locatelli5,7, Irene Bozzoni1,3,4,8, Elisabetta Ferretti9,10, Elisa Caffarelli1,3
1Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy
2Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
3Institute of Molecular Biology and Pathology, National Research Council, 00185 Rome, Italy
4Department of Biology and Biotechnology, Sapienza University of Rome, 00185 Rome, Italy
5Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
6Department of Neuroscience and Neurorehabilitation, Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
7University of Pavia, Corso Strada Nuova, 27100 Pavia, Italy
8Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, 00185 Rome, Italy
9Department of Experimental Medicine Sapienza University of Rome, 00161 Rome, Italy
10Neuromed Institute, 86077 Pozzilli, Italy
11Present addresses: Center for Genomic Regulation, 08003 Barcelona, Spain
12Present addresses: Virology Program, INGM-Istituto Nazionale di Genetica Molecolare, 20122 Milan, Italy
13Present addresses: Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
Elisa Caffarelli, email: email@example.com
Elisabetta Ferretti, email: firstname.lastname@example.org
Keywords: long noncoding RNAs, competing endogenous RNAs, microRNAs, cancer driver genes, Group 4 medulloblastoma
Received: September 14, 2016 Accepted: February 27, 2017 Published: March 09, 2017
Long noncoding RNAs (lncRNAs) are major regulators of physiological and disease-related gene expression, particularly in the central nervous system. Dysregulated lncRNA expression has been documented in several human cancers, and their tissue-specificity makes them attractive candidates as diagnostic/prognostic biomarkers and/or therapeutic agents. Here we show that linc-NeD125, which we previously characterized as a neuronal-induced lncRNA, is significantly overexpressed in Group 4 medulloblastomas (G4 MBs), the largest and least well characterized molecular MB subgroup. Mechanistically, linc-NeD125 is able to recruit the miRNA-induced silencing complex (miRISC) and to directly bind the microRNAs miR-19a-3p, miR-19b-3p and miR-106a-5p. Functionally, linc-NeD125 acts as a competing endogenous RNA (ceRNA) that, sequestering the three miRNAs, leads to de-repression of their targets CDK6, MYCN, SNCAIP, and KDM6A, which are major driver genes of G4 MB. Accordingly, linc-NeD125 downregulation reduces G4 cell proliferation. Moreover, we also provide evidence that linc-NeD125 ectopic expression in the aggressive Group 3 MB cells attenuates their proliferation, migration and invasion.
This study unveils the first lncRNA-based ceRNA network in central nervous system tumours and provides a novel molecular circuit underlying the enigmatic Group 4 medulloblastoma.
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